The Tumor Microenvironment and Metastasis Program focuses on the interactions between cancer cells and their microenvironment that are determinants of the potential of tumor cells to invade surrounding tissues, penetrate blood vessels, and ultimately enter and grow in distant tissues. Studies are directed to deciphening the signaling pathways and mechanical interactions among monocytes, macrophages, endothelial cells and carcinoma cells, and each of their supporting stroma, which contribute to the metastatic phenotype. The goals of the program are to: (1) Dissect the role the microenvironment in tumor progression and metastasis, in particular, the contribution of macrophage subpopulations to the various phases and elements of tumor progression; 2) to elucidate the molecular mechanisms of growth factor and cytokine action in regulating cell migration, dissemination, angiogenesis and invasion of distant sites by primary tumor cells; 3) to assess the role of surface molecules, such a cadherins and membrane surface oligosaccharides, in tumor progression; (4) to characterize the biochemical and structural properties of molecules that regulate cytoskeletal proteins involved in tumor cell and macrophage motility through the development of (i) fluorescent biosensors of the activity status of pathways involved in regulating cell migration in vivo and (ii) photo-switchable proteins for quantitative long-term tracking of distinct groups of cells photomarked in the primary tumor and (5) to translate these findings into correlative studies with human tissues that are predictive of metastatic potential and risk, and that identify therapeutic targets. New imaging technologies are developed in the Gruss Lipper Biophotonics Center that provides this program with unique tools that are made available to the broader AECC community through the Analytical Imaging Shared Resource. Intrinsic to the experimental approach is the development of novel mouse transgenic models with fluorescently-labeled cellular lineages. The research by members of this program is integrated by a major shared focus on breast cancer, although other tumor types are studied as well. Research in this program is supported, in part, by a program project grant which reflects, and furthers, the collaborative research of members of this program. There are currently 24 members from 11 departments, of whom 10 are new to the program, supported by 22 NCI grants ($4.1M Direct) and 18 other peer-reviewed cancer-relevant grants ($3.5M Direct). Since the last CCSG review there have been 239 cancer-relevant research papers by members of this program of which 23% represent intraprogrammatic, and 28% represent interprogrammatic publications.